Myelodysplastic syndrome (MDS) is a group of diseases characterized by clonal abnormalities in hematopoietic stem cells that cause hematopoietic function failure and a high risk of progression to acute myeloid leukemia (AML). The disease is divided into five types, namely, refractory anemia (RA), ring-shaped sideroblastic anemia, refractory anemia with excess of blasts (RAEB), refractory anemia with excess of blasts in transformation (RAEB-T) and chronic myelomonocytic leukemia (CMML).
In Europe and America, the incidence of MDS is 4 per 100,000 each year, which is twice the incidence of AML. In the elderly population over 70 years old, the incidence of MDS can reach 20 per 100,000. In China, the incidence of this disease has increased due to the extension of the average life expectancy and the aging of the population. Generally, the supportive therapy is used to control the progression of the disease in patients with low risk of MDS, while effective medicaments or therapies are needed for the treatment of patients with high risk of MDS due to poor prognosis.
Azacitidine is a DNA methyltransferase inhibitor that can cause DNA hypomethylation and has a direct cytotoxicity, developed by Pharmion Pharmaceuticals, USA. In May 2004, the US FDA approved the drug Vidaza for marketing for the treatment of all subtypes of MDS. Due to the rapid hydrolysis of the active ingredient azacitidine in water, the substances related to the lyophilized preparation are difficult to control, and the stability of the product during storage is poor, which has a potential impact on the safety and efficacy of clinical medication.
Patent CN103251564A discloses an azacitidine for injection and the preparation method thereof, which mainly controls the pH value of aqueous solution of azacitidine by using hydrochloric acid or sodium hydroxide and reduces related substances of the product after lyophilization. However, in the preparation process of the present invention, it is necessary to add activated carbon and keep the temperature at 80° C. in a water bath for 20 minutes, and then removing the activated carbon by filtration. It is well known that activated carbon tends to leak and remain during filtration, brings a potential safety risk. Therefore, it is still necessary to provide a method with a simple process and stable quality.
Patent CN101632643A discloses an azacitidine for injection and the preparation method thereof, which attempts to increase the stability of the product in aqueous solution by using vitamin C as a stabilizer. However, activated carbon still needs to be added in the preparation process, and thus leakage and residue problems of the activated carbon during filtration cannot be avoided. In addition, vitamin C is a component that not included in the original product, and the introduction of a new component may cause an unnecessary safety problem for the injection.
Patent US20110042247 discloses a preparation method of azacitidine for injection, comprising 1) cooling 95% sterile water to −1 to −3° C.; 2) adding mannitol and stirring to dissolve; 3) adding azacitidine with the desired quality and stirring the mixture to form a solution; 4) controlling the final temperature at −3° C. and stirring for 5 minutes until the solution is clear; 5) filtering the solution through a 0.2 μm sterile filter; 6) bottling and lyophilizing. It is well known that circulating condensed water is commonly used in production at present, and it is impossible to perform circulating cooling since water is easily crystallized at −1 to −3° C. Therefore, it is often necessary to replace a cooling solvent such as absolute ethanol, which often brings danger to production and increases production cost since absolute ethanol is flammable and explosive.
Therefore, it is still necessary to provide a new solution to overcome the above disadvantages, such that the azacitidine for injection has a simple process for production and qualified quality, and is beneficial to commercial production.